The long-term goal ofthe research program. Genetic Models for Precision Cancer Medicine (Drs. Bult, Dai, and McKeon co-Leaders), is to develop novel therapeutic and diagnostic concepts for cancer by modeling and interrogating the complex genomics of human cancers. Research is organized around three inter-related themes, all of which involve the systems genomics ofthe cancer cell and its host environment. The first theme. Cancer Cell Robustness, aims to define the dynamic genome alterations at a systems level that generate primary drug resistance in a cancer and its subclones. The second theme. Genetic and Genomic Complexity, aims to measure and quantify genomic instability in primary cancers; to describe the associated genomic configurations; and to use defective maintenance systems for genome integrity for therapeutic advantage. The third theme. Progenitor Cell Biology, aims to define the genomic parameters of certain cancer progenitors; to reconstruct cancer states in primary cells using systems approaches; and to use this knowledge to provide effective combinatorial therapeutics. All program goals rely on interactions with program members who are developing advanced cross cutting technological approaches. The first approach, precision model development, includes efficient methods for humanizing cancer-relevant genomic regions in the mouse; tool strains for directing and visualizing temporal and tissue-specific gene expression; optimized immunodeficient mice for sustained engraftment of primary human cancers; and populations of mice that model human genomic heterogeneity. The second approach, genomic technologies, develops new high throughput DNA interrogation methodologies for detailed assessment of structural and sequence mutations and their transcriptional consequences. The third key technology is computational, including algorithms for modeling gene networks; ontology development that supports data integration and enables in silico modeling of gene functional associations; and informatics and database systems are essential for integrative studies and comparative genomic analyses. The 47 program members include 35 at Bar Harbor, 8 at Farmington, and 1 at Sacramento, together with 3 adjunct members from UC Davis Comprehensive Cancer Center, Eastern Maine Healthcare Systems, and Trinity University (TX). Through its emphasis on basic research and unique technology development, the program leverages funding from multiple NIH ICs in support of cancer focused research. In total the program is supported by $40,150,131 total costs in NCI and other peer reviewed cancer-related support in the last budget year. Over the past grant cycle, program members produced 1022 publications, including 10% intra-programmatic collaborations and 62% with collaborators external to JAX